Palladium-Catalyzed Direct (Het)arylation Reactions of Benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole and 4,8-Dibromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole)

Palladium-catalyzed direct (het)arylation reactions of strongly electron-withdrawing tricyclic benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) and its 4,8-dibromo derivative were studied; the conditions for the selective formation of mono- and bis-aryl derivatives were found. The reaction of 4,8-dibromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) with thiophenes in the presence of palladium acetate as a catalyst and potassium pivalate as a base, depending on the conditions used, selectively gave both mono- and bis-thienylated benzo-bis-thiadiazoles in low to moderate yields; arenes were found to be inactive in these reactions. It was discovered that direct C–H arylation of benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole with bromo(iodo)arenes and -thiophenes in the presence of Pd(OAc)2 and di-tert-butyl(methyl)phosphonium tetrafluoroborate salt is a powerful tool for the selective formation of 4-mono- and 4,8-di(het)arylated benzo-bis-thiadiazoles. Oxidative double C–H hetarylation of benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole with thiophenes in the presence of Pd(OAc)2 and silver (I) oxide in DMSO was successfully employed to prepare bis-thienylbenzo-bis-thiadiazoles in moderate yields.


Results and Discussion
The optimal conditions for the selective synthesis of mono-4 and bis-5 coupling products were calculated for the reaction of 4,8-dibromobenzo[1,2-d:4,5-d ]bis([1,2,3]thiadiazole) 2 with (2-ethylhexyl)thiophene 3a in the presence of various palladium catalysts and organic ligands. The results of this study are summarized in Table 1. It was found that by using Pd(OAc) 2 with potassium pivalate as a base in toluene, both mono-4a-and bis-aryl derivatives 5a can be obtained. The nature of the solvent and ligand, the temperature of the chemical transformation, and the excess of the reagent significantly affected the results of the reactions (Table 1). Unexpectedly, carrying out the reaction in the frequently used solvent DMA [17][18][19][20] resulted only in the decomposition of the starting dibromide 2 ( Table 1, entry 1). Refluxing in the aromatic solvent, toluene, led to the disappearance of the starting bicycle 2 with the formation of the target product 4a in moderate yield  (Table 1, entry 2). An increase in the reaction temperature to 130 • C and an increase in the amount of the starting thiophene to two equivalents gave bis-coupling product 5a in a yield close to that of mono-product 4a (Table 1, entry 3). An unexpected fact was that the use of ligands such as tri-tert-butylphosphine (Bu t 3 P), bis(diphenylphosphino)ferrocene (dppf) or XPhos, PBu t 2 MeHBF 4 , both in toluene and in DMA, stopped the formation of products 4a and 5a; in these cases, the starting heterocycle 2 decomposed slowly under the reaction conditions (Table 1, entries 4-9). The optimal conditions were extended to other thiophene derivatives 3b-d; mono-and bis-dithienylated derivatives were isolated in moderate yields (Table 1, entries [12][13][14][15][16][17]. Attempts to carry out the C-H arylation reaction involving aromatic compounds such as toluene or xylene using various catalytic systems were not successful; starting dibromide 2 was isolated in high yields. Thus, we have shown that the C-H arylation reactions of dibromide 2 proceeded only with heteroaromatic thiophene derivatives 3a-d and selectively led to the formation of mono-and bis-thienyl derivatives in moderate yields. as a base in toluene, both mono-4а-and bis-aryl derivatives 5а can be obtained. The nature of the solvent and ligand, the temperature of the chemical transformation, and the excess of the reagent significantly affected the results of the reactions (Table 1). Unexpectedly, carrying out the reaction in the frequently used solvent DMA [17][18][19][20] resulted only in the decomposition of the starting dibromide 2 ( Table 1, entry 1). Refluxing in the aromatic solvent, toluene, led to the disappearance of the starting bicycle 2 with the formation of the target product 4a in moderate yield (Table 1, entry 2). An increase in the reaction temperature to 130 °C and an increase in the amount of the starting thiophene to two equivalents gave bis-coupling product 5a in a yield close to that of mono-product 4a ( Table 1, entry 3). An unexpected fact was that the use of ligands such as tri-tert-butylphosphine (Bu t 3P), bis(diphenylphosphino)ferrocene (dppf) or XPhos, PBu t 2MeHBF4, both in toluene and in DMA, stopped the formation of products 4a and 5a; in these cases, the starting heterocycle 2 decomposed slowly under the reaction conditions (Table 1, entries 4-9). The optimal conditions were extended to other thiophene derivatives 3b-d; mono-and bis-dithienylated derivatives were isolated in moderate yields ( Table 1, entries [12][13][14][15][16][17]. Attempts to carry out the C-H arylation reaction involving aromatic compounds such as toluene or xylene using various catalytic systems were not successful; starting dibromide 2 was isolated in high yields. Thus, we have shown that the C-H arylation reactions of dibromide 2 proceeded only with heteroaromatic thiophene derivatives 3a-d and selectively led to the formation of mono-and bis-thienyl derivatives in moderate yields.  Palladium-catalyzed direct arylation reactions of non-halogenated aromatic electronwithdrawing heterocycles are much less studied. The results of the reaction of tricycle without the formation of target products 7a and 5a ( Table 2, entry 1). The introduction of such ligands as tri-tert-butylphosphine (But 3 P) or bis(diphenylphosphino)ferrocene (dppf) did not activate the cross-coupling reaction (Table 2, entries 3,4), but the employing of XPhos led to the formation of a monocoupling product 7a with a low yield ( Table 2, entry 2). The use of such palladium catalysts as tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), and bis(triphenylphosphine)palladium chloride (PdCl 2 (PPh 3 ) 2 ) also did not run the cross-coupling reaction ( Table 2, entries 5,6,8). The best results were shown by a catalytic system based on (Pd(OAc) 2 ) and di-tertbutyl(methyl)phosphonium tetrafluoroborate salt (P(Bu t ) 2 MeHBF 4 ) [36]. If the reaction of benzo[1,2-d:4,5-d ]bis([1,2,3]thiadiazole) 1 was carried out in refluxing toluene in the presence of potassium pivalate, then the bis-coupling product 7a was formed ( Table 2, entry 9). Long-term reflux in toluene in the presence of Pd(OAc) 2 and P(Bu t ) 2 MeHBF 4 led to the formation of compound 7a in 45% yield (Table 2, entry 10). It was shown that the replacement of toluene by higher boiling xylene (130 • C) shifted the C-H arylation reaction towards the bis-coupling product 5a in a good yield of 55% ( Table 2, entry 11). The use of DMA or DMF as a solvent did not lead to the formation of cross-coupling products ( Table 2, entries 12,13). Treatment of tricyle 1 with one equivalent of 2-iodo-5-(2-ethylhexyl)thiophene in the presence of Pd(OAc) 2 ) and P(Bu t ) 2 MeHBF 4 ) led to the formation of a mixture of mono-7a and bis-5a substituted products in a ratio of 2:1 ( Table 2, entry 14). Increasing the amount of iodine derivative 6a(I) to two equivalents and replacing toluene with xylene resulted in the selective formation of the bis-coupling product 5a in 54% yield (Table 1, entry 15). 2-Chloro-5-(2-ethylhexyl)thiophene gave under these conditions the mono-coupling product 7a in trace amounts of 2% (Table 2, entry 16). Palladium-catalyzed direct arylation reactions of non-halogenated aromatic electron-withdrawing heterocycles are much less studied. The results of the reaction of tricycle 1 with 2-bromo-5-(2-ethylhexyl)thiophene 6a(Br) as a halogen-containing substrate are summarized in Table 2. Refluxing in toluene in the presence of palladium acetate (Pd(OAc)2) and potassium pivalate (PivOK) resulted in partial decomposition of the starting bicycle 1 without the formation of target products 7а and 5а (Table 2, entry 1). The introduction of such ligands as tri-tert-butylphosphine (But3P) or bis(diphenylphosphino)ferrocene (dppf) did not activate the cross-coupling reaction ( Table 2, entries 3,4), but the employing of XPhos led to the formation of a monocoupling product 7a with a low yield ( Table 2, entry 2). The use of such palladium catalysts as tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and bis(triphenylphosphine)palladium chloride (PdCl2(PPh3)2) also did not run the cross-coupling reaction ( Table 2, entries 5,6,8). The best results were shown by a catalytic system based on (Pd(OAc)2) and di-tert-butyl(methyl)phosphonium tetrafluoroborate salt (P(Bu t )2MeHBF4) [36]. If the reaction of benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) 1 was carried out in refluxing toluene in the presence of potassium pivalate, then the bis-coupling product 7a was formed (Table 2, entry 9). Long-term reflux in toluene in the presence of Pd(OAc)2 and P(Bu t )2MeHBF4 led to the formation of compound 7a in 45% yield ( Table 2, entry 10). It was shown that the replacement of toluene by higher boiling xylene (130 °C) shifted the C-H arylation reaction towards the bis-coupling product 5a in a good yield of 55% ( Table 2, entry 11). The use of DMA or DMF as a solvent did not lead to the formation of cross-coupling products ( Table 2, entries 12,13). Treatment of tricyle 1 with one equivalent of 2-iodo-5-(2-ethylhexyl)thiophene in the presence of Pd(OAc)2) and P(Bu t )2MeHBF4) led to the formation of a mixture of mono-7a and bis-5a substituted products in a ratio of 2:1 ( Table 2, entry 14). Increasing the amount of iodine derivative 6a(I) to two equivalents and replacing toluene with xylene resulted in the selective formation of the bis-coupling product 5a in 54% yield (  The optimal conditions for the cross-coupling reaction (Pd(OAc) 2 and PBu t 2 MeHBF 4 catalytic system in refluxing toluene at 110 • C or in xylene at 130 • C) were extended to halogenated derivatives of thiophene and benzene 6b-j. If for 2-bromothiophenes 6a-c,e(Br) the hetarylation reactions proceeded selectively and with moderate yields of both mono-7 and bis-5 products, then for bromoarenes the chemical transformation led to a lower yield of mono-and bis-coupling products (Table 3, entries 9,10). The replacement of bromobenzene 6f(Br) by the more reactive iodobenzene 6f(I) made it possible to significantly increase the yield of both mono-coupling 7f and bis-coupling 5f products (Table 3, entries 11,12). It was shown that the use of iodobenzenes 6(I) in the reaction with tricycle 1 gave the target products 7 and 5 in moderate yields ( Table 3, entries 13-20). The optimal conditions for the cross-coupling reaction (Pd(OAc)2 and PBu t 2MeHBF4 catalytic system in refluxing toluene at 110 °C or in xylene at 130 °C) were extended to halogenated derivatives of thiophene and benzene 6b-j. If for 2-bromothiophenes 6a-c,e(Br) the hetarylation reactions proceeded selectively and with moderate yields of both mono-7 and bis-5 products, then for bromoarenes the chemical transformation led to a lower yield of mono-and bis-coupling products (Table 3, entries 9,10). The replacement of bromobenzene 6f(Br) by the more reactive iodobenzene 6f(I) made it possible to significantly increase the yield of both mono-coupling 7f and bis-coupling 5f products (Table 3, entries 11,12). It was shown that the use of iodobenzenes 6(I) in the reaction with tricycle 1 gave the target products 7 and 5 in moderate yields (Table 3, entries 13-20). Oxidative hetarylation reactions of tricycle 1 with thiophene derivatives were studied using (2-ethylhexyl)thiophene 3a, palladium trifluoroacetate and acetate as catalysts under the action of silver (I) oxide (Ag 2 O) as an oxidizing agent in dimethyl sulfoxide as described for BTD derivatives (see Scheme 1,path 3). Surprisingly, palladium trifluoroacetate did not catalyze this hetarylation reaction (Table 4, entry 1). The use of palladium acetate instead of palladium trifluoroacetate led to the formation of a mixture of mono-7a and bis-5a coupling products (Table 4, entry 2). We investigated the possibility of replacing silver oxide with silver salts such as silver acetate (AgOAc), silver nitrate (AgNO 3 ), silver tetrafluoroborate (AgBF 4 ), and silver perchlorate (AgClO 4 ). It was shown that in the case of silver acetate, the total yield of the mixture of products 7a and 5a was only 25%, while in the case of silver nitrate, compound 5a was isolated in 4% yield, and the use of silver tetrafluoroborate and silver perchlorate did not lead to the formation of thienylated products (Table 4, entries 3-6). Reducing the amount of thiophene derivative 3a to one equivalent also gave a mixture of mono-and bis-derivatives in low yield with a significant predominance of mono-derivative 7a (Table 4, entry 7) and using three equivalents of 3a, together with increasing the reaction time to 48 h, gave the highest yield of bis-product 5a, 55% ( Table 4, entry 8). These conditions were extended to other thiophene derivatives 3b,c,e, to produce bis-coupling products 5 in moderate to low yields ( Table 4, entries [10][11][12]. Attempts to carry out the reaction of oxidative arylation with benzene and toluene were unsuccessful; as a result, only a gradual decomposition of the starting tricycle 1 was observed.
Two other variants of the direct (het)arylation reaction turned out to be more useful for preparation of (het)arylbenzo-bis-thiadiazoles. Thus, path 7, the direct arylation reaction of benzo-bis-thiadiazole 1 with halogenated thiophenes and arenes, makes it possible to obtain mono-derivatives 7, which are inaccessible by other methods. Despite the fact that the yields of bis-aryl derivatives 5 in path 8 are somewhat lower (20-55%) than in the Suzuki and Stille reactions (paths 2 and 4), one should take into account the fact that dibromotricycle 2 is obtained from unsubstituted tricycle 1 with a yield of 40% [12], which practically equalizes the yields in the preparation of compounds 5 from unsubstituted tricycle 1 by its bromination followed by Suzuki and Stille reactions (paths 2 and 4) and direct (het)arylation with bromo(iodo)arenes and thiophenes (path 8). When comparing these methods, it should be taken into account that in direct (het)arylation there is no need to obtain boronic esters and trialkylstannyl derivatives, which usually require the use of flammable butyllithium and harmful tin compounds.
Oxidative hetarylation of compound 1 may be of particular interest for the preparation of bis-hetaryl derivatives 5Th. Readily accessible heterocycle 1 and often commercially available thiophenes are involved in the reaction, which makes it possible to significantly reduce the number of steps in the synthesis of bis-thienylated benzo-bis-thiadiazoles 5Th practically without reducing their yields. An important advantage of the last two variants of direct hetarylation (paths 8 and 9) is the selectivity of these processes, which greatly simplifies the procedure for isolating the final compounds. We found that refluxing dibromide 2 and tricycle 1 in toluene for 24 h resulted in their We recently found that Stille coupling of 4,8-dibromobenzo [1,2-d:4,5-d ]bis( [1,2,3] thiadiazole) 2 gave good yields of bis-arylated heterocycles 4 (55-73%, path 3), and the Suzuki-Miyaura reaction led to the selective formation of both mono-4 (60-72%, path 1) and bis-(het)arylated 5 (50-67%, path 2) benzo [1,2-d:4,5-d ]bis([1,2,3]thiadiazoles) [12]. In this paper, we have shown that direct arylation of dibromotricycle 2 is successful only for thiophene derivatives and afforded approximately two times lower yields of mono-4Th (31-43%, path 5) and bis-5Th products (29-40%, path 6); arenes did not react with tricycle 2 at all. Even if we take into account that the yields of boronic esters and tributylstannyl thiophene derivatives from unsubstituted thiophenes are known to be below 100%, it seems that this direct arylation variant (paths 5 and 6) cannot compete with the Suzuki and Stille reactions for compound 2 (paths 1-4).
Two other variants of the direct (het)arylation reaction turned out to be more useful for preparation of (het)arylbenzo-bis-thiadiazoles. Thus, path 7, the direct arylation reaction of benzo-bis-thiadiazole 1 with halogenated thiophenes and arenes, makes it possible to obtain mono-derivatives 7, which are inaccessible by other methods. Despite the fact that the yields of bis-aryl derivatives 5 in path 8 are somewhat lower (20-55%) than in the Suzuki and Stille reactions (paths 2 and 4), one should take into account the fact that dibromotricycle 2 is obtained from unsubstituted tricycle 1 with a yield of 40% [12], which practically equalizes the yields in the preparation of compounds 5 from unsubstituted tricycle 1 by its bromination followed by Suzuki and Stille reactions (paths 2 and 4) and direct (het)arylation with bromo(iodo)arenes and thiophenes (path 8). When comparing these methods, it should be taken into account that in direct (het)arylation there is no need to obtain boronic esters and trialkylstannyl derivatives, which usually require the use of flammable butyllithium and harmful tin compounds.
Oxidative hetarylation of compound 1 may be of particular interest for the preparation of bis-hetaryl derivatives 5Th. Readily accessible heterocycle 1 and often commercially available thiophenes are involved in the reaction, which makes it possible to significantly reduce the number of steps in the synthesis of bis-thienylated benzo-bis-thiadiazoles 5Th practically without reducing their yields. An important advantage of the last two variants of direct hetarylation (paths 8 and 9) is the selectivity of these processes, which greatly simplifies the procedure for isolating the final compounds. We found that refluxing dibromide 2 and tricycle 1 in toluene for 24 h resulted in their partial decomposition to a mixture of unidentifiable compounds, which, in turn, may also be the cause of low or moderate yields of C-H arylation reaction products.

Materials and Reagents
The chemicals were purchased from commercial sources (Sigma-Aldrich, St. Louis, MO, USA) and used as received. Benzo [1,2- [40], and [2,2 -bithiophen]-5-yltrimethylsilane 6e [41] were prepared according to the published methods and characterized by NMR spectra. All synthetic operations were performed under a dry argon atmosphere. Toluene and xylene were distilled over Na. DMSO was distilled over CaH 2 .
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28093977/s1. Characterization data including 1 H and 13 C NMR spectra for novel compounds.
Author Contributions: O.A.R. and T.N.C. conceived and designed the study; T.N.C., D.A.A. and T.A.K. performed the experiments; T.N.C. analyzed the data. All authors contributed to writing and editing the paper. All authors have read and agreed to the published version of the manuscript.

Funding:
We gratefully acknowledge financial support from the Russian Science Foundation (Grant no. 22-23-00252).